This project began with compelling theoretical evidence and intriguing empirical hints to support our innovative hypothesis that schizophrenia (SZ) is associated with learning and temporal processing deficits linked to dysfunction of the cerebellum (CB) and related circuits. In the intervening years we found striking empirical evidence in SZ of behavioral dysfunction on several CB-dependent tasks, including associative learning (eyeblink conditioning), motor timing (finger tapping), and time perception (temporal bisection). Moreover, we found that 1st-degree relatives of SZ patients and individuals with schizotypal personality disorder also exhibit associative learning deficits. Finally, correlations between performance on CB-dependant tasks and cognitive functioning support contemporary models of the role of the CB in cognition. Taken together, our findings of learning and temporal processing deficits dovetail elegantly with emerging evidence of structural and functional CB abnormalities in SZ, and warrant further investigation for several important reasons. First, we must determine whether the observed behavioral deficits are associated with direct evidence of functional and structural CB abnormalities. We will use fMRI to investigate whether task-related CB activation predicts behavioral performance deficits in SZ across three tasks: eyeblink conditioning, finger tapping, and temporal bisection. Second, it is critical to determine whether SZ is associated with impaired cortico-CB connectivity. We will use MRI to examine resting-state functional connectivity and DTI-based structural connectivity between the CB and select cerebral regions that normally have strong neuroanatomical connections with the CB-though it is not known if this is the case in SZ-and are thought to be involved in temporal processing. Task-related fMRI dynamic causal modeling will be used to study directional influences between brain regions. Third, it is critical to understand whether neuroimaging dependent variables predict cognitive performance, so we have selected a battery of tasks with strong evidence of CB involvement. Fourth, our preliminary evidence that CB-dependent eyeblink conditioning is impaired in 1st-degree relatives of SZ patients and in schizotypal personality disorder begs the question of whether CB abnormalities represent endophenotypes of SZ. Forty individuals with SZ and 40 of their 1st-degree relatives will complete a battery of tasks to address these questions. Their performance will be compared to age- and sex-matched non-psychiatric control subjects (N=80). Successfully completing the proposed research will determine: (1) whether CB dysfunction underlies behavioral abnormalities observed in SZ on associative learning and temporal processing tasks;and (2) whether CB abnormalities represent endophenotypes of SZ. Our data will critically inform models of CB involvement in cortical cognitive processing in psychiatric illness and yield insights about potential novel mechanisms of illness and targets of treatment.

Public Health Relevance

This study will lead to improved understanding of the neural mechanisms underlying schizophrenia, which is an extraordinarily debilitating psychological disorder. The resulting knowledge will be especially informative about the role of an understudied region of the human brain called the cerebellum, and may lead to the identification and development of innovative treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH074983-07
Application #
8537505
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Meinecke, Douglas L
Project Start
2005-07-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
7
Fiscal Year
2013
Total Cost
$374,400
Indirect Cost
$134,400
Name
Indiana University Bloomington
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Kim, Dae-Jin; Davis, Elysia Poggi; Sandman, Curt A et al. (2014) Longer gestation is associated with more efficient brain networks in preadolescent children. Neuroimage 100:619-27
O'Bryan, Rebecca A; Brenner, Colleen A; Hetrick, William P et al. (2014) Disturbances of visual motion perception in bipolar disorder. Bipolar Disord 16:354-65
Dominelli, Rachelle M; Boggs, Jennifer M; Bolbecker, Amanda R et al. (2014) Affect modulated startle in schizophrenia: subjective experience matters. Psychiatry Res 220:44-50
Bolbecker, Amanda R; Westfall, Daniel R; Howell, Josselyn M et al. (2014) Increased timing variability in schizophrenia and bipolar disorder. PLoS One 9:e97964
Kim, Dae-Jin; Kent, Jerillyn S; Bolbecker, Amanda R et al. (2014) Disrupted modular architecture of cerebellum in schizophrenia: a graph theoretic analysis. Schizophr Bull 40:1216-26
Cheng, H; Skosnik, P D; Pruce, B J et al. (2014) Resting state functional magnetic resonance imaging reveals distinct brain activity in heavy cannabis users - a multi-voxel pattern analysis. J Psychopharmacol 28:1030-40
Kent, Jerillyn S; Michael Bailey, D; Vollmer, Jennifer M et al. (2013) A magnetic resonance imaging-safe method for the study of human eyeblink conditioning. J Neurosci Methods 216:16-21
O'Donnell, Brian F; Vohs, Jenifer L; Krishnan, Giri P et al. (2013) The auditory steady-state response (ASSR): a translational biomarker for schizophrenia. Suppl Clin Neurophysiol 62:101-12
Motz, Benjamin A; Erickson, Molly A; Hetrick, William P (2013) To the beat of your own drum: cortical regularization of non-integer ratio rhythms toward metrical patterns. Brain Cogn 81:329-36
Kam, Julia W Y; Bolbecker, Amanda R; O'Donnell, Brian F et al. (2013) Resting state EEG power and coherence abnormalities in bipolar disorder and schizophrenia. J Psychiatr Res 47:1893-901

Showing the most recent 10 out of 27 publications